DESCRIPTION (From Abstract): Cyclooxygenase (COX), also known as prostaglandin G/H synthase, catalyzes the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been identified. COXI is constitutively expressed in many tissues including platelets, endothelial cells, the gastrointestinal tract and kidney. COX2 is an inducible immediate early gene whose expression in macrophages is induced by inflammatory stimuli. COX2 is also found in neurons, where its expression is induced by synaptic activity and blocked by excitatory amino acid antagonists (1,2). In preliminary studies, we have shown that expression of COX2 mRNA and protein is increased in hippocampal CA1 neurons destined to die after global cerebral ischemia, CA3 neurons destined to die after kainate-induced seizures, and cortical neurons destined to die after temporary focal cerebral ischemia, in rats. In both ischemia and epilepsy, death of these vulnerable neurons may be prevented by treatment with a selective inhibitor of COX2 activity, SC58125. Moreover, there is preliminary data that COX2 inhibitors are protective in primary neuronal culture subjected to transient hypoglycemia and hypoxia. The hypothesis to be tested is that COX2 activity contributes to ischemic neuronal injury. Specific Aims are to 1) confirm whether COX2 activity contributes to neuronal injury after ischemia in vivo. 2) determine the effect of COX2 inhibitors on cell death and generation of reactive oxygen species in primary neuronal cultures subjected to transient hypoglycemia/hypoxia. 3) Determine the effect of COX2 inhibitors and COX2 gene disruption on ROS formation and oxidative damage to lipids, protein and DNA after ischemia. 4) Determine the effect of COX2 inhibitor treatment and COX2 gene disruption on thromboxane synthesis, neutrophil accumulation and blood brain barrier permeability. Many drugs that selectively inhibit COX2 are being developed as effective nonsteroidal anti-inflammatory drugs (NSAIDs) without the renal, hematological and gastrointestinal toxicity of common nonselective NSAIDs. Accordingly, our results suggest that COX2 inhibition has promise as a nontoxic treatment for ischemia and other neurologic diseases where excitotoxicity and oxidative stress have been implicated.